In women, breast cancer is among the most common cancers and is the fifth most common cause of cancer deaths. Due to the heterogeneity of breast cancers, 10-year progression free survival can vary widely with stage and type, from 98% to 10%. Different forms of breast cancers can have remarkably different biological characteristics and clinical behavior. Thus, classification of a patient's breast cancer has become a critical component for determining a treatment regimen. For example, along with classification of histological type and grade, breast cancers now are routinely evaluated for expression of hormone receptors (estrogen receptor (ER) and progesterone receptor (PR)) and for expression of HER2 (ErbB2), since a number of treatment modalities are currently available that target hormone receptors or the HER2 receptor. ER and PR are both nuclear receptors (they are predominantly located at cell nuclei, although they can also be found at the cell membrane) and small molecular inhibitors that target ER and/or PR have been developed. HER2, or human epidermal growth factor receptor type 2, is a receptor normally located on the cell surface and antibodies that target HER2 have been developed as therapeutics. HER2 is the only member of the EGFR family (which also includes HER1 (EGFR), HER3 (ErbB3) and HER4 (ErbB4) that is not capable of binding to an activating ligand on its own. Thus HER2 is only functional as a receptor when incorporated into a heterodimeric receptor complex with another EGFR family member, such as HER3. Cancers classified as expressing the estrogen receptor (estrogen receptor positive, or ER+ tumors) may be treated with an ER antagonist such as tamoxifen. Similarly, breast cancers classified as expressing high levels the HER2 receptor may be treated with an anti-HER2 antibody, such as trastuzumab, or with a HER2-active receptor tyrosine kinase inhibitor such as lapatinib.
Triple negative (TN) breast cancer is a term used to designate a well-defined clinically relevant subtype of breast carcinomas that account for approximately 15% of all breast cancer cases. TN tumors score negative (i.e., using conventional histopathology methods and criteria) for expression of ER and PR and do not express amplified levels of HER2 (i.e., they are ER−, PR−, HER2−). TN breast cancer comprises primarily, but not exclusively, a molecularly and histopathologically distinct subtype of breast cancer known as the basal-like (BL) subtype. The BL subtype also is characterized by the expression of cytokeratins (e.g., CK, CK5/6, CK14, CK17) and other proteins found in normal basal/myoepithelial cells of the breast. However, in addition to the BL subtype, certain other types of breast cancers, including some “normal breast-like”, metaplastic carcinomas, medullary carcinomas and salivary gland-like tumors can also exhibit the triple negative (TN) phenotype. Furthermore, TN breast cancers occur more frequently in the presence of BRCA1 mutations and in pre-menopausal females of African-American or Hispanic descent. TN tumors typically display very aggressive behavior, with shorter post-relapse survival and poor overall survival rates relative to other breast cancer types.
Not all BL breast cancers are TN. Basal-like breast tumors are a heterogeneous tumor type that account for up to 15% of all breast cancers and exhibit aggressive clinical behavior that makes them particularly difficult to treat successfully. A majority of BL breast cancers are ER-, PR-, and HER2 low (HER21+ or HER2 negative). In addition, they typically express proteins usually found in normal breast basal (myoepithelial) cells. These include high molecular weight cytokeratins (e.g., 5/6, 8, 14, 17 and 18), p-cadherin, caveolins 1 and 2, nestin, aB crystalline, and EGFR. Furthermore, BL tumor cells typically lack the capacity for competent homologous recombination DNA repair.
Histologically, most BL breast cancers are of IDC-NST type, high histological grade, and exhibit very high mitotic indices. They also typically have central necrotic or fibrotic zones, pushing borders, conspicuous lymphocytic infiltrates, and typical/atypical medullary features, and generally exhibit features similar to those of human papilloma virus-induced squamous cell carcinoma of the head and neck.
A great majority of medullary and atypical medullary, metaplastic, secretory, myoepithelial, and adenoid cystic carcinomas of the breast also exhibit BL characteristics.
Given the lack of expression of hormone receptors or of significant amounts of HER2 in TN breast cancer cells, treatment options have been very limited as the tumors are not responsive to treatments that target ER (e.g., tamoxifen, aromatase inhibitors) or HER2 (e.g., trastuzumab). Instead these tumors are treated with conventional neoadjuvant and adjuvant chemotherapy regimens, which have limited efficacy and many cytotoxic side effects. Furthermore, such chemotherapy regimens can lead to drug resistance in tumors, and the risk of recurrence of disease in TN breast cancers is higher within the first three years of treatment than for other types of breast cancers.
Basal-like breast cancers are also difficult to treat and are associated with poor prognoses, though BL adenoid cystic carcinomas generally are associated with better clinical outcomes.
In view of the foregoing, a need remains for additional treatment options and methods for treating triple negative breast cancers and BL breast cancers.